Semifluorinated compounds

ABSTRACT

The present invention is directed to certain semifluorinated compounds and to compositions comprising such compounds. The invention further provides the use of the compounds and of the compositions as medicaments for topical administration to the eye.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to European Patent ApplicationNos. 15187760.2 filed Sep. 30, 2015, and 15192429.7 filed Oct. 30, 2015,each of which are incorporated by reference in their entireties.

DESCRIPTION Field

The present invention is in the field of semifluorinated compounds,compositions thereof, and their use as a medicine in particular forophthalmic administration.

Background

Semifluorinated alkanes are compounds composed of at least onenon-fluorinated hydrocarbon segment and at least one perfluorinatedhydrocarbon segment. Linear, unbranched semifluorinated alkanes of thegeneral formula CF₃(CF₂)_(n)(CH₂)_(m)CH, wherein n and m are integersdenoting the number of carbon atoms of the respective segment aredescribed for various applications, for example commercially forunfolding and reapplying a retina, for long-term tamponade as vitreoushumour substitute (H. Meinert et al., European Journal of Ophthalmology,Vol. 10(3), pp. 189-197, 2000), and as wash-out solutions for residualsilicon oil after vitreo-retinal surgery.

Semifluorinated alkanes of the formula CF₃(CF₂)_(n)(CH₂)_(m)CH₃ aredescribed in other applications.

WO 2011/073134 discloses solutions of ciclosporin in a semifluorinatedalkanes of the formula CF₃(CF₂)_(n)(CH₂)_(m)CH₃, optionally in thepresence of a co-solvent such as ethanol, wherein the semifluorinatedalkane functions as a liquid drug delivery vehicle for ciclosporin fortopical treatment of keratoconjunctivitis sicca.

WO2014/041055 describes mixtures of semifluorinated alkanes of theformula CF₃(CF₂)_(n)(CH₂)_(m)CH₃ (which may be alternatively expressedas F(CF₂)_(n)(CH₂)_(m)H). These mixtures are described to beophthalmically applicable as tear film substitutes or for treatingpatients with dry eye syndrome and/or meibomian gland dysfunction.

A nomenclature which is frequently used for semifluorinated compoundshaving linear and unbranched segments is FnHm, wherein F means aperfluorinated hydrocarbon segment, H means a non-fluorinated segment,and n and m define the number of carbon atoms of the respective segment.For example, F3H3 is used for perfluoropropylpropane, CF₃(CF₂)₂(CH₂)₂CH₃, i.e. 1-perfluoropropylpropane.

Semifluorinated alkanes of the general formulaCF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ however have not been described, inparticular for ophthalmic applications. It is therefore an object of theinvention to provide such compounds, in particular in respect of theiruse in compositions, especially with utility in the field of ophthalmicapplications.

SUMMARY OF THE INVENTION

In a first aspect, the invention relates to compositions comprising asemifluorinated compound characterized by the general formulaCF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ wherein n is an integer selectedfrom 3 to 5 and m is an integer selected from 1 to 5. Preferably, thesecompositions are in the form of a liquid, wherein the compositionscomprise at least 1 wt %, in particular from 1 wt % to 5 wt % of acompound characterized by CF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ wherein nis an integer selected from 3 to 5 and m is an integer selected from 1to 5.

In another aspect, the present invention relates to compositionscomprising said compounds in the form of clear, liquid solutions, andalso compositions which essentially consist of said compounds andoptionally one or more lipophilic liquid constituents.

In still another aspect, the invention provides the use of compositionscomprising said compounds for treatment of dry eye disease and/orMeibomian Gland Dysfunction and any symptoms or conditions associatedtherewith.

In a further aspect, the present invention provides a method fortreatment of dry eye disease and any symptoms or conditions associatedtherewith, comprising administering said composition topically to thelacrimal sac, into the lower eyelid, to an eye surface or to anophthalmic tissue.

In a yet further aspect, the present invention provides a kit comprisingcompositions of the present invention held in a container whichcomprises dispensing means adapted for topical administration of thecomposition to the eye or ophthalmic tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the relative evaporation time ofcompositions consisting of the compounds CF₃(CF₂)₅(CH₂)₇CH₃ andCF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ as a function of the percentage of thelatter compound in the composition (indicated by the solid circle anddotted line in the graph), and the relative evaporation time ofcompositions consisting of the compounds CF₃(CF₂)₃(CH₂)₄CH₃ andCF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃ as a function of the percentage of thelatter compound in the composition (indicated by the transparent circleand dashed line in the graph).

FIG. 2 is a graph depicting the refractive index determined forcompositions consisting of the compounds CF₃(CF₂)₅(CH₂)₇CH₃ andCF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ as a function of the percentage of thelatter compound in the composition.

FIG. 3 is a graph depicting the refractive index determined forcompositions consisting of the compounds CF₃(CF₂)₃(CH₂)₄CH₃ andCF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃ as a function of the percentage of thelatter compound in the composition.

FIG. 4 is a graph representing the corneal erosion size measurements(mm²) over the course of three days of an Ex vivo Eye Irritation Test(EVEIT) comparison of compositions comprising CF₃(CF₂)₅(CH₂)₇CH₃ andCF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃, a hyaluronic standard reference and 0.01%BAC positive control.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the invention relates to a semifluorinated compoundcharacterized by the general formula CF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃wherein n is an integer selected from 3 to 5 and m is an integerselected from 1 to 5.

Particularly preferred compounds of the formulaCF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ are those in which n is 5 and m is 5(i.e. formula CF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃), or wherein n is 3 or and mis 2 (i.e. formula CF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃). Other preferredcompounds include CF₃—(CF₂)₃—CH(CH₃)—(CH₂)₃—CH₃,CF₃—(CF₂)₃—CH(CH₃)—(CH₂)₅—CH₃, CF₃—(CF₂)₅—CH(CH₃)—(CH₂)₁—CH₃, andCF₃—(CF₂)₅—CH(CH₃)—(CH₂)₃—CH₃.

Alternatively, the compounds of the invention may be also generally bereferred to as 2-perfluoroalkylalkanes, for instance, the compoundCF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ may also be referred to as2-perfluorohexyloctane, based on the hydrocarbon alkane as the root.

The compounds feature a stereocenter at the 2-alkyl position. Asunderstood herein, the general formula encompasses both enantiomers,enriched mixtures of the two enantiomers, as well as the racemicmixture.

It has been found that compounds as defined above provide a number ofunexpected advantages, as outlined below. They are particularly usefulwhen provided as compositions such as for medical applications, inparticular for topical administration, such as topical ophthalmicadministration.

The present invention relates to compositions comprising thesesemifluorinated compound characterized by the general formulaCF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ as defined above are preferably inthe liquid form, for example formulated to be administered as a liquidsolution. In optional embodiments, the compositions may be formulated tobe administered as a gel, suspension, microemulsion, or a spray.Preferably, the compositions are provided in sterile form.

In a particularly preferred embodiment, compositions comprising asemifluorinated compound characterized by the general formulaCF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ wherein n is an integer selectedfrom 3 to 5 and m is an integer selected from 1 to 5 is in a liquid formand comprises at least 1 wt % of the compound, in particular from 1 wt %to 5 wt %, based on the total weight of the composition. In otherembodiments, the composition may comprise between about 3 wt % to 5 wt%, or about 5 wt % to 10 wt %, or up to 25 wt % of the compound based onthe total weight of the composition.

In one of the preferred embodiments, the composition as defined above isformulated as a clear, liquid solution. In this context, clear means theabsence of dispersed solid or liquid particles which cause turbidity. Inother words, such clear solution is a purely monophasic liquid system,except that minor and technically irrelevant amounts of particulateimpurities may be present.

Moreover, the composition is preferably formulated as a liquid solutionwhich exhibits a refractive index that is close to that of water whichis 1.333 at room temperature (RT). In a particularly preferredembodiment, the refractive index of the liquid solution is in the rangeof from about 1.30 to about 1.35 at 20° C., as determined byrefractometer.

The compositions as defined above may also comprise further excipientsas required or as useful, such as one or more acids, bases,electrolytes, buffers, solutes, antioxidants, stabilizers, and ifrequired, preservatives. In one preferred embodiment, the compositionsas defined above are substantially free of water and/or substantiallyfree of a preservative, such as benzalkonium chloride.

In another preferred embodiment, the composition of the invention isformulated as clear liquid solution that is substantially free of thefollowing: (a) a polymer (b) a perfluorinated compound, and/or (c) adissolved pharmacologically active ingredient which is not asemifluorinated alkane. In another embodiment, the composition asdescribed herein may be substantially free of a pharmacologically activeingredient in any form and which is not a semifluorinated alkane.

As understood herein, the term ‘substantially free’ in reference to acomposition constituent refers to the presence of said constituent in nomore than trace amounts and that if present in trace amounts theconstituent provides no technical contribution to the composition.

Examples of polymers which are preferably absent in the compositions ofthe invention include silicone polymers (polymerized siloxanes),polyether polymers and fluorinated or perfluorinated derivativesthereof.

Examples of perfluorinated compounds, i.e. compounds in which all thehydrogen atoms are replaced with fluorine, and which are preferablyabsent in the compositions of the invention include perfluoroalkanessuch as perfluorodecalin, as well as halogenated perfluoroalkanes suchas perfluorooctylbromide.

The compositions of the invention that are in the form of a clear liquidsolution are also substantially free of a dissolved pharmacologicalactive ingredient which is not a semifluorinated alkane. As used herein,the term “pharmacological active ingredient” refers to any type ofpharmaceutically active compound or drug, i.e. one that produces apharmacological effect and that may accordingly be useful in theprevention, diagnosis, stabilization, treatment, or generally speaking,the management of a condition or disease.

The compounds of the invention as well as the compositions comprisingthese, even if free of other pharmacologically active ingredients,however have beneficial therapeutic effects at the site ofadministration.

In a further preferred embodiment, the compositions of the inventionessentially consist of a compound characterized by the general formulaCF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ wherein n is an integer selectedfrom 3 to 5 and m is an integer selected from 1 to 5, and optionally,one or more lipophilic liquid constituents. In a particular embodiment,the composition consists essentially of either the compoundCF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ or CF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃, or amixture thereof, and optionally one or more lipophilic liquidconstituents.

As used herein, the term “essentially consisting of” is so-called closedlanguage, meaning that only the mentioned constituents are present. Incontrast, the terms “comprise”, “comprises” and “comprising” are usedherein as so-called open language, meaning that further constituents mayalso be present.

The optional lipophilic liquid constituents are preferably substantiallynon-water soluble and/or non-water miscible excipients, for example oilyexcipients such as lipids, triglyceride oils and any other oils that arephysiologically tolerated by the eye, or other semifluorinated alkanessuch as in the class belonging to the general formulaCF₃(CF₂)_(n)(CH₂)_(m)CH₃, wherein n and m are integers independentlyselected from the range of 3 to 8, for example, CF₃(CF₂)₃(CH₂)₄CH₃ orCF₃(CF₂)₅(CH₂)₇CH₃.

Such lipophilic liquid constituents may be present in the composition inamounts up to about 25 wt % or up to about 50 wt %, or 75 wt % or 90 wt%, 95 wt % or 97 wt % of the composition, based on total weight of thecomposition.

In a further preferred embodiment, the composition according to thepresent invention comprises or essentially consists ofCF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ and CF₃—(CF₂)₅—(CH₂)₇—CH₃, or ofCF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃ and CF₃—(CF₂)₃—(CH₂)₄—CH₃

The compositions as defined above are preferably formulated to have adynamic viscosity of not more than 10 mPa·s, and preferably not morethan 4 mPa·s, as determined under standard ambient temperature andpressure (25° C., 1 atm). Preferably, the compositions have a dynamicviscosity of between 1 and 4 mPa·s. The viscosity of the compositionsmay be determined using any standard viscometer device known in the art,such as a glass tube or capillary viscometer.

The compounds characterized by the general formulaCF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ wherein n is an integer selectedfrom 3 to 5 and m is an integer selected from 1 to 5 and compositionsthereof as described herein may be used in medical applications, inparticular for use in ophthalmology, in particular in the topicaladministration to the eye, such as to the lacrimal sac, into the lowereyelid, to an eye surface or to any ophthalmic tissue or anatomyassociated with the eye that may be made available for topicaladministration.

In particular, the compounds of the invention are beneficial for use inthe treatment of diseases and conditions which would benefit fromstabilization of the tear film and tear film lipid layer and lubricationof the eye surface. Thus, the compositions of the present invention areespecially suited in the treatment of dry eye disease(keratoconjunctivitis sicca) and/or Meibomian Gland Dysfunction (MGD)and any symptoms thereof or associated therewith.

Dry eye disease, also known as keratoconjunctivitis sicca, can bedistinguished into two categories, namely aqueous deficient dry eyedisease and evaporative dry eye disease. These conditions are notnecessarily mutually exclusive. Aqueous deficient dry eye is typicallyobserved in patients suffering from Sjögren syndrome, or those sufferingfrom a lacrimal gland insufficiency, lacrimal duct obstruction or reflexhyposecretion. Evaporative dry eye disease on the other hand has diverseroot causes and is associated with increased/abnormal evaporative lossof the tear film, for example as a result of meibomian gland disorders,eyelid aperture disorders, blinking disorders, or ocular surfacedisorders.

Symptoms of dry eye disease include dry, scratchy, gritty, sandy orforeign body sensations in the eye; pain, soreness, stinging or burning;itching, increased need for blinking, eye fatigue, photophobia, blurryvision, redness and inflammation of the eye tissue, excess mucusdischarge and crusting/clotting, contact lens intolerance, and excessreflex tearing.

Meibomian Gland Dysfunction (MGD) refers to a condition where themeibomian glands do not secrete enough oil, or when the oily secretionis of poor or abnormal quality. Often, the oil gland openings may becomeplugged up and obstructed so that less oil is secreted from the glands.The oil that is secreted from the glands can be granular (crusty) orotherwise abnormal, and can cause irritation to the eye. In the earlystages, patients are often asymptomatic, but if left untreated, MGD cancause or exacerbate dry eye symptoms and eyelid inflammation. The oilglands become blocked with thickened secretions. Chronically cloggedglands eventually become unable to secrete oil, which may result inpermanent changes in the tear film and dry eyes.

Symptoms of Meibomian Gland Dysfunction include dryness, burning,itching, stickiness/crustiness, watering, light sensitivity, red eyes,foreign body sensation, chalazion/styes or intermittent blurry vision.

In a preferred embodiment of the invention, the compounds andcompositions thereof as described above are used for the topicalophthalmic treatment of evaporative dry eye disease and/or MeibomianGland Dysfunction, and relief of any one of the symptoms associatedtherewith.

In one embodiment of the invention, the ophthalmic compositioncomprising of a semifluorinated compound characterized by the generalformula CF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ wherein n is an integerselected from 3 to 5 and m is an integer selected from 1 to 5; orpreferably, wherein n is 5 and m is 5 (i.e. formulaCF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃), or wherein n is 3 or and m is 2 (i.e.formula CF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃), are used for the treatment ofdry eye disease (keratoconjunctivitis sicca) or a symptom associatedtherewith. In another embodiment, such composition may be used for thetreatment of Meibomian Gland Dysfunction or a symptom associatedtherewith.

In further embodiments, the treatment of these conditions is preferablycarried out by a method of administering to a patient in need thereof,an effective amount of a composition essentially consisting of saidsemifluorinated alkane, and optionally one or more lipophilic liquidconstituents that are preferably substantially non-water soluble and/ornon-water miscible excipients, for example oily excipient such aslipids, triglyceride oils and any other oils that are physiologicallytolerated by the eye, or other semifluorinated alkanes such as in theclass belonging to the general formula CF₃(CF₂)_(n)(CH₂)_(m)CH₃, whereinn and m are integers independently selected from the range of 3 to 8,for example, CF₃(CF₂)₃(CH₂)₄CH₃ or CF₃(CF₂)₅(CH₂)₇CH₃.

In a further preferred embodiment of the invention, the compounds andcompositions thereof as described above are used for the topicalophthalmic treatment of corneal damage. Thus, said compounds andcompositions are actively supporting the corneal healing process ofcorneal damage, such as corneal erosions.

The advantages of the compounds described above in the context of theiruse according to the present invention are believed to relate to theirproperties which are particularly suited for ophthalmic applications.The close proximity of the refractive indices of the compounds of theinvention to that of water, means that there would be no or minimalimpact of a patient's vision subsequent to administration, unlikeophthalmic compositions based on oily carriers which can confer blurryvision on administration. The generally low viscosity and low surfacetension and in particular their high wetting and spreading capabilitiesof these compounds also ensures that they are rapidly accommodated andadapted on administration over the surface of the eye.

As will be made clearer in the examples below, it was found that thecompounds and compositions thereof are biocompatible and exhibit noapparent cytotoxic effects. Moreover, it has been established that saidcompounds and their compositions are not only well tolerated in the eye,but also provide a beneficial effect in terms of lubrication of the eyeand stabilization of the tear film, in the form of relief in symptoms ofpatients having mild to moderate symptoms associated with dry eyedisease and/or Meibomian Gland Dysfunction. Patients with dry eyedisease and/or dysfunctional meibomian glands often express opaque andthicker meibum which can lead to an abnormal lipid layer in the tearfilm. Without wishing to be bound to theory, it is believed that thephysico-chemical attributes of the compounds of the invention may play arole in stabilizing the lipid layer of the tear film, such as bysolubilization of certain lipid components or improving the fluidity ofthe lipid layer.

In a further aspect, the present invention provides a method fortreatment of dry eye disease and any symptoms or conditions associatedthereof comprising administering the compositions of the presentinvention topically to the lacrimal sac, into the lower eyelid, to aneye surface or to an ophthalmic tissue. Preferably, said compositionscan be administered to the eye or eye tissue up to four times per day.

Furthermore, the invention provides a kit comprising any one of thecompositions as described above, and a container for holding saidcomposition. Said container preferably comprises a dispensing meansadapted for topical administration of the composition to an eye sac,lower eyelid to an eye or ophthalmic tissue, such as an eye dropper.

In a further preferred embodiment, the dispensing means comprises adropper of dimensions such as to dispense droplets having a volume ofabout 8 to 15 μl, preferably having a volume of about 8-12 μl, morepreferably having a volume of about 10 μl. With a small droplet volume,precise dosing to the eye can be achieved and an excess amount ofdischarge of a substantial fraction of the composition from the eyesubsequent to administration can be avoided.

EXAMPLES Preparation of CF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃(2-Perfluorohexyl-octane. C₁₄F₁₃H₁₇)

The compound CF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ may be prepared as follows:radical addition of perfluorohexyl iodide with 1-octene in the presenceof a radical initiator (herein perfluorohexyl iodide is mixed with1-octene and a radical initiator as AIBN and the obtained solution ismaintained at 80° C. for 30 min and cooled down), followed by reductionof the resulting iodo adduct with hydride (i.e. LiALH₄) or viahydrogenation (i.e. catalytic hydrogenation in presence of a catalystsuch as Pd/C) to form 2-perfluorohexyl-octane, followed by purificationby fractional distillation. Other compounds of formulaCF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ as defined above may be preparedanalogously by this general method.

CF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃: ¹H-NMR (CDCl₃, 400 MHz): 2.17-2.33 (m,1H, CH), 1.67-1.77 (m, 2H, CH₂), 1.25-1.40 (m, 8H, CH₂), 1.15 (d, 3H,CH₃), 0.90 (t, 3H, CH₃).

Preparation of CF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃ (2-Perfluorobutyl-pentane,C₉F₉H₁₁)

The compound CF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃ may be prepared according tothe general method described above with perfluorobutyl iodide and1-pentene as the starting materials.

CF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃: ¹H-NMR (CDCl₃, 400 MHz): 2.21-2.32 (m,1H, CH), 1.68-1.74 (m, 2H, CH₂), 1.45-1.55 (m, 2H, CH₂), 1.12 (d, 3H,CH₃), 0.92 (t, 3H, CH₃).

In Vitro Cytotoxicity Assay

The cytotoxicity of a composition comprising 1.3 wt %CF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ and 95.8 wt % CF₃(CF₂)₅(CH₂)₇CH₃ wasassessed by a cell growth inhibition test which predicts cytotoxic ornecrotic effects with good correlation to animal experiments and highsensitivity.

The composition was extracted by cell culture medium (DMEM supplementedwith 10% FBS) under agitation for ˜24 hours. The resulting extract wasthen incubated with mouse cell line L929 cells for 68-72 hours, beforethe protein content was analyzed using a BCA (bicinchoninic acid) testas a measure for cytotoxicity. No inhibition of cell growth or celllysis was observed.

An analogous in vitro cytotoxicity assay is conducted for a compositioncomprising about 23.7 wt % CF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ and about 75.6wt % F6H8.

Tear Film Analysis Studies

A composition comprising 98.3 wt % of CF₃(CF₂)₅(CH₂)₇CH₃ and 1.2 wt % ofCF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ was tested in an observational study inpatients with mild to moderate evaporative dry eye disease. The clearcolorless liquid composition was provided in a 5 ml bottle equipped witha dropper dimensioned to dispense droplets of ˜10 μl per drop into theeye sac. Patients wearing contact lenses were excluded from the study.After informed consent had been obtained, patients were advised to apply3-4 drops, daily in both eyes, translating to a daily dose of 30-40 μl.Patients returned after 5-7 weeks for follow-up. Clinical data for 29patients were collected at baseline and at the 5-7 week follow-up visit.

a) Tear Film Analysis

Tear film fluid and tear film stability improved over the study period,as can be seen in the increase in Schirmer I and the TFBUT. Theretrospective statistical analysis is strengthening this observation, asthe difference in TFBUT at baseline and follow-up is highly significant(paired two-sided t-test: p=0.0026 (right eyes) and p=0.0006 (lefteyes)). No changes were detected in tear osmolarity.

The subjective dry eye questionnaire (Ocular Surface Disease Index,OSDI) revealed that patient's subjective symptom severity decreasedafter the use of the composition comprising 98.3 wt % ofCF₃(CF₂)₅(CH₂)₇CH₃ and 1.2 wt % of CF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ over a5-7 week period, as can be seen in the lower scores at follow-up and theretrospective statistical analysis (paired two sided t-test: p<0.0001).

Parameter Baseline Follow up Schirmer I (mm/5 min)/  10.7 ± 3.7  16.3 ±8.9 Right eye TFBUT (sec) Right eye: 5.7 ± 2.6 Right eye: 7.9 ± 5.1 Lefteye: 5.7 ± 2.6 Left eye: 8.6 ± 6.0 Osmolarity 315.7 ± 12.8 311.4 ± 14.7OSDI  53.9 ± 22.5  35.8 ± 22.9

b) Corneal Staining (Oxford Grading Scheme)

Corneal fluorescein staining is an indicator of corneal damage (loss ofcell-to-cell junctions). The data indicate a reduction of corneal damageafter 5-7 weeks of treatment, as can be seen in the shift of numbers ofpatients diagnosed with Grade 1 or 2 at baseline towards Grade 0 atfollow-up. This difference to the initial level of damage wasstatistically significant, as shown by Wilcoxon signed rank test:p=0.0013 (right eyes) and p=0.0041 (left eyes).

Baseline (n = 29) Follow up (n = 28) Grade 0 Grade 1 Grade 2 Grade 0Grade 1 Grade 2 Right eye (n) 8(1) 16 4 25 2 1 Left eye (n) 8(1) 16 4 199 0

c) Symptom Assessment by Physician

Patients were asked by the physician whether they currently suffer fromtypical dry eye symptoms both at the baseline and at the follow-upvisit. As can be seen in the table below, a lower number ofDED-associated symptoms were reported after 5-7 weeks of treatment.

Baseline Follow up Red eyes 25 9 Itching 21 10 Clotted eyes 9 2 Stringymucous 4 1 Headache 2 1

d) Meibum Secretion Analysis

In a healthy eye, meibum is secreted from the meibomian glands as aclear liquid. More opaque and thicker meibum is an indicator ofdysfunctioning meibomian glands. Patients' meibum was descriptivelyexamined at both the baseline and the follow-up visit. According to thedata obtained, meibum quality improved in a number of cases. In sevencases, the treatment induced a reduction of expressible meibum (changingfrom clear meibum to none).

Baseline Follow up Clear 20 17 Whitish 6 3 Thick 1 0 None 2 9

e) Safety Parameters

No changes were seen in either visual acuity or intraocular pressure,indicating that the use of composition comprising 98.3 wt % ofCF₃(CF₂)₅(CH₂)₇CH₃ and 1.2 wt % of CF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ over5-7 weeks is safe and does not interfere with these ophthalmologicalparameters.

Baseline Follow up Visual acuity 0.8 (0.7-1.0) 0.9 (0.8-1.0) Intraocularpressure 14.9 ± 2.6 14.6 ± 3.2 (mm HG)

Differential Scanning Calorimetry

Differential Scanning calorimetry (DSC 1, Mettler Toledo, Greifensee,Switzerland) is used to characterize structure and phase behavior ofmixtures of CF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ and CF₃(CF₂)₅(CH₂)₇CH₃. DSC wasemployed to obtain data on transitions by temperature rising scans withheating rate of 1° C./min. Sealed standard aluminum crucibles (40 μl,Mettler Toledo) were used.

wt % CF₃—(CF₂)₅— Melting transition CH(CH₃)—(CH₂)₅— ΔH Onset Peak EndsetCH₃ (J/g) (° C.) (° C.) (° C.) 0 −36.57 −6.33 −4.53 −2.14 5.91 −33.36−10.32 −7.99 −7.24 12.03 −29.42 −13.74 −10.44 −9.58 23.74 −24.09 −21.56−15.38 −14.17

wt % Low temperature transition CF₃(CF₂)₅—CH(CH₃)— ΔH Onset Peak Endset(CH₂)₅—CH₃ (J/g) (° C.) (° C.) (° C.) 0 −0.69 −45.47 −40.37 −38.32 5.91−0.56 −50.61 −45.77 −42.93 12.03 −0.44 −55.18 −48.58 −45.53 23.74 −0.19−60.75 −54.39 −52

The presence of CF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ in a mixture ofCF₃(CF₂)₅—(CH₂)₇—CH₃ (F6H8) resulted in a significant reduction in themelting temperature. The melting enthalpy is also decreased, whichsuggests that this semifluorinated alkane does not crystallize. Suchdifferences will have a beneficial effect in respect of the applicationof this compound to the eye as a tear film substitute or lubricant; forexample, in terms of its ability to mix with, and to modulate the tearfilm lipid layer. Such effects can moreover be advantageously tuned byvarying the amounts of the compound which are added to ophthalmiccompositions.

DSC measurements of a series of mixtures of 23.74 wt % ofCF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ and CF₃(CF₂)₅(CH₂)₇CH₃ with tetradecane(C14) was also performed. Data on transitions were obtained withtemperature rising scans (heating rates 0.2, 0.5 and 1° C./min).Extrapolation to a heating rate of 0° C./min was used to determineendset temperatures while average from the three measurements were usedto determine onset temperatures. A decrease in the melting enthalpy wasobserved, compared to mixtures of tetradecane with pureCF₃(CF₂)₅(CH₂)₇CH₃, suggesting that some of the tetradecane is dissolvedin the liquid fraction of CF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ and that thiscompound has a stronger solubilizing capacity compared to CF₃(CF₂)₅(CH₂)₇CH₃.

Refractive Index and Evaporation Time

The evaporation time of mixtures of the semifluorinated alkaneCF₃(CF₂)₃(CH₂)₄CH₃ (F4H5) and CF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃ wasevaluated. A droplet of 10 μL volume of each mixture was placed on aglass surface at room temperature. Time until evaporation was recordedby video-monitoring.

CF₃(CF₂)₃ CF₃—(CF₂)3— Relative (CH₂)₄CH₃/ CH(CH₃)— EvaporationEvaporation Sample % (CH₂)₂—CH₃/% time/s Time 1 99.95 0.00 304 1.00 296.85 2.99 302 0.998 3 0.00 95.13 322 1.064

It was observed that an increased amount of the compoundCF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃ appears to increase the evaporation timeof the mixture (see FIG. 1).

The evaporation time of mixtures of the semifluorinated alkaneCF₃(CF₂)₅(CH₂)₇CH₃ (F6H8) and CF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ was evaluatedanalogously.

CF₃(CF₂)₅ CF₃(CF₂)₅— Relative (CH₂)₇CH₃/ CH(CH₃)— EvaporationEvaporation Sample % (CH₂)₅—CH₃/% time/s Time 1 99.84 0.16 13260 1 296.53 3.05 12960 0.97 3 26.3 64.1 9960 0.75

In contrast, it was unexpectedly observed that an increasing percentageof the semifluorinated alkane CF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ significantlydecreases the evaporation time of the mixtures (see FIG. 1).

Thus, depending on the compound characterized by the general formulaCF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ wherein n is an integer selectedfrom 3 to 5 and m is an integer selected from 1 to 5 and amount presentin the mixture, it may feasible to adapt and fine-tune the compositionto the requirements of the intended ophthalmic use, such as in terms ofprolonging or reducing the residence time of the composition on the eyesurface.

The refractive index of the mixtures was also determined. For topicallyapplied ophthalmic compositions, the refractive index of the compositionshould preferably be similar, or adapted to that of the eye and lens,for instance as close to that of physiological tear fluid as possible.If the refractive index of a composition is not similar, when applied tothe surface of the eye, a patient may experience blurring or impairedvision. It is observed, that the amount of the compoundCF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ or has an effect on refractive index. FIG.2 depicts an increasing refractive index value with increased content ofthe 2-perfluorohexyl-octane in a mixture with 1-perfluorohexyl-octane.FIG. 3 likewise depicts an increasing refractive index value withincreasing content of 2-perfluorobutyl-pentane in a mixture with1-perfluorobutylpentane.

By varying the amount of these compounds, such as characterized by thegeneral formula CF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ wherein n is aninteger selected from 3 to 5 and m is an integer selected from 1 to 5 inthe mixture, it may also be feasible to adapt the composition to therequirements of the intended ophthalmic use, for instance adapting to apatient with altered tear fluid composition and refractive index due toan eye condition and/or age.

Ex vivo Eye Irritation Test (EVEIT)

A comparison in respect of corneal healing process was conducted for twocompositions comprising CF₃(CF₂)₅(CH₂)₇CH₃, namely compositionsconsisting of a mixture of the semifluorinated alkane CF₃(CF₂)₅(CH₂)₇CH₃and CF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ (Composition A with 0.17 wt % ofCF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ and Composition B, with 64 wt % ofCF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃) with hyaluronic acid (HYLO-COMOD®) as areference and 0.01% BAC (benzalkonium chloride) as a positive controlusing an Ex Vivo Eye Irritation Test (EVEIT), similar to as described inM. Frentz et al, Altern. to Lab. Anim., 2008 (36) p 25-32; and N.Schrage et al, Graefes Arch Clin Exp Ophthalmol 2012 (250), 1330-1340).

Method. Rabbit corneas were obtained and placed in an artificialanterior ocular chamber which was gently filled with serum-free minimalessential medium (Eagle's MEM) containing Earle's salts and HEPES bufferfor nutrition. The medium was contstantly replenished by a micropump toimitate the physiological condition of the eye. The culture chamberswere held at 32° C. under normal air without supplementary CO2 and >95%relative humidity. Five corneas per test substance (n=5) were usedexcept for the postive control with which two corneas (n=2) were tested.

After 12 h of stabilization in the culture chamber, the corneas wereevaluated by microscopy and corneas with intact epithelium and withoutopacities were selected. Four small abrasions (2.3-4.3 mm²) were appliedto the surface of the selected corneas with a cornea drill. All defectswere monitored by fluorescein sodium staining (0.17% aq. solution) andmicroscopy.

The test substances were administered one hour after induction of thecorneal erosion and were applied six times daily onto the apex of thecorneas (30-50 μL every four hours). A soft-tipped cannula, withcontinuous suction was placed on the lowest part of the corneoscleralregion within the culturing chamber to remove any excess fluid.Experiments were terminated after 3 days of application. Biomicroscopicimages of the corneas were taken daily to document the corneal healingprocess using a phase-contrast microscope integrated camera (KY-F1030U,JVC, (Bad Vilbel, D E) mounted on a Z16 APO Microscope (Wetzlar, D E)).All defects were monitored by fluorescein sodium stains (0.17% aq.solution) with yellow green fluorescence indicating the areas ofepithelial defects. Erosion sizes were determined using a software toolof the microscope (DISKUS). At the end of the 3 days, the experiment wasterminated and all corneas were fixed in 3.7% formaldehyde and stainedwith a hematoxylin-eosin dye for microscopic evaluation. To monitor themetabolic activity of the cornea, glucose and lactate concentrationswere photometrically quantified in the outflow medium from theartificial anterior chambers.

Results. Both mixtures of the semifluorinated alkanes (Composition A andB as referenced above) were observed to have a similar positive effectin respect of the corneal healing process after the induction of cornealerosion as compared with the standard reference hyaluronic acidcomposition (HYLO-COMOD®).

Corneal Erosion Size Measurements/Mean mm² (SD)

Composition Day 0 Day 1 Day 2 Day 3 A (n = 5)  12.8 (0.98) 3.018 (0.89)  0 (0) 0 (0) B (n = 5) 12.23 (1.46)  3.59 (0.53)   0 (0) 0 (0) HYLOCOMOD ® 12.13 (1.29)  3.11 (0.76) 0.01 (0.02) 0 (0) 0.01% BAC 11.57(0.86)  5.91 (0.28) 8.74 (7.6) 17.46 (6.43)

Day 3 Histological Observations

Com- position A (n = 5) Multilayered epithelium and dense stroma in allcorneas. Keratocytes are well formed and arranged except if lost frominitial erosion area. Descemet membrane appears intact, endothelialcells are present. B (n = 5) Healed epithelial layer with closedmultilayer of epithelial cells. Dense stroma and regular formedkeratocytes although typically reduced in number under the initialerosion area. Descemet membrane and endothelial layer present withoutstructural defects Hylo Multilayered epithelium and dense stroma withregular Comod ® arranged and formed keratocytes except under the initial(reference) erosion areas where keratocytes are totally lost in theupper stroma. Descemet membrane and endothelial layer are presentwithout any defects in structure. 0.01% Severe alterations of thesuperficial cornea with BAC disintegration of whole corneal structures;observation of (positive distinct edema control) Reduced staining ofbackground substance indicating chemical alteration of collagen Severereduction in number of keratocyte cells which also appear rounded andpycnotic. Descemet membrane is present with intact endothelium

No significant differences in terms of a positive corneal healing wasnoted between composition B comprising 64 wt %, based on total weight ofthe composition of semifluorinated alkane CF₃(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃and composition A. With both compositions, as with the referencecomposition, the mechanically induced epithelial erosions were found tobe significantly reduced and essentially absent after day 2 oftreatment. FIG. 3 depicts the corneal erosion size measurements of thetested compositions, reference and positive controls for days 0-3 of theEVEIT experiment.

As noted in the table above, microscopic histological examination of thecross-sections of the corneas after termination of the experiment on day3 revealed no significant remaining defects or differences in thecorneas treated with compositions A, B and the reference HYLO-COMOD®.

Furthermore, no corneal toxicity, based on the metabolic activity asindicated by the glucose/lactate measurements was observed for thesecompositions.

In significant contrast, the positive control comprising 0.01% of thepreservative BAC, a progressive increase of the induced epitheliallesions was observed over the course of the three days of theexperiment.

1-13. (canceled)
 14. A composition comprising a compound of the generalformulaCF₃—(CF₂)_(n)—CH(CH₃)—(CH₂)_(m)—CH₃ wherein n is an integer selectedfrom 3 to 5 and m is an integer selected from 1 to
 5. 15. Thecomposition according to claim 1, wherein (i) n is 5 and m is 5, (ii) nis 3 and m is 2, (iii) n is 3 and m is 3, (iv) n is 3 and m is 5, or (v)n is 5 and m is
 1. 16. The composition according to claim 15, whereinthe composition is in liquid form, or in the form of a liquid solution.17. The composition according to claim 15, wherein the compositioncomprises at least 1 wt % and/or up to 25 wt % of the compound, based onthe total weight of the composition.
 18. The composition according toclaim 15, wherein the composition is substantially free of water and/orsubstantially free of a preservative.
 19. The composition according toclaim 15, wherein the composition consists essentially of the compound,and optionally one or more lipophilic liquid constituents selected fromnon-water-soluble and/or water-miscible excipients.
 20. The compositionaccording to claim 19, wherein the one or more lipophilic liquidconstituents are selected from lipids, triglyceride oils, oils that arephysiologically tolerated by the eye, and semifluorinated alkanes of theformula CF₃—(CF₂)_(n)—CH₂)_(m)—CH₃, wherein n and m are independentlyselected from 3 to
 8. 21. the composition according to claim 20, whereinthe semifluorinated alkanes are selected from CF₃—(CF₂)₃—(CH₂)₄—CH₃ andCF₃—(CF₂)₅—(CH₂)₇—CH₃.
 22. The composition according to claim 19,wherein the composition comprises the one or more lipophilicconstituents in an amount up to 25 wt % or up to 97%.
 23. Thecomposition according to claim 15, wherein the composition consistsessentially of CF₃—(CF₂)₅—CH(CH₃)—(CH₂)₅—CH₃ and CF₃—(CF₂)₅—(CH₂)₇—CH₃,or of CF₃—(CF₂)₃—CH(CH₃)—(CH₂)₂—CH₃ and CF₃—(CF₂)₃—(CH₂)₄—CH₃.
 24. Thecomposition according to claim 16, wherein the composition is a liquidsolution having a refractive index of 1.30 to 1.35 at 25° C., asdetermined by refractometer.
 25. The composition according to claim 15,wherein the composition has a dynamic viscosity of not more than 10mPa-s, as determined at 25° and 1 atmosphere pressure.
 26. A method oftreating a disease or condition of a patient in need of such treatment,comprising administering the composition according to claim 14 to thepatient.
 27. The method according to claim 26, wherein the compositionis administered topically to the patient.
 28. The method according toclaim 27, wherein the composition is topically administered to thelacrimal sac, into the lower eyelid, to an eye surface or to anophthalmic tissue.
 29. The method according to claim 26, wherein thecomposition is administered as a gel, suspension, microemulsion, orspray.
 30. The method according to claim 26, wherein the disease orcondition is dry eye disease (keratoconjunctivitis sicca) and/orMeibomian Gland Dysfunction and any symptoms thereof or associatedtherewith.
 31. A kit comprising a composition according to claim 14 anda container for holding the composition.
 32. The kit according to claim33, wherein the container comprises dispensing means adapted for topicaladministration of the composition to an eye sac, to the lower eyelid, toan eye, or to an ophthalmic tissue.
 33. The kit according to claim 32,wherein the dispending means comprises a dropper for dispending dropletsof 8 to 15 μl.